Vascular disease is the principal cause of morbidity and mortality in patients with diabetes, leading to nephropathy, retinopathy, neuropathy, and ischemic disease. Hyperglycemic damage to vascular endothelial cells is a major cause of these vascular complications of diabetes. This endothelial dysfunction is caused by oxidative stress induced by hyperglycemia, resulting in both the increased production of reactive oxygen species (ROS) and decreased bioavailability of nitric oxide (NO). Hyperglycemia also causes similar oxidative stress in renal mesangial cells, which leads to mesangial matrix expansion, glomerosclerosis, and renal functional impairment. We have developed a novel drug for treatment of hyperglycemia induced endothelial and mesangial cell dysfunction. OX029 is a bifunctional NO-donor/SOD-mimetic which is a derivative of lipoic acid, The major goals of this proposal are to (1) determine the efficacy of OX029 to prevent endothelial dysfunction and renal injury in the diabetic streptozotocin-treated rat, and (2) design and synthesize 20 novel analogs of OX029 and test their efficacy in isolated blood vessels and cultured renal mesangial cells exposed to hyperglycemia. If OX029 is efficacious in preventing renal injury in STZ-diabetic rats, we plan to submit a Phase II grant to: (1) test one or two OX029 analogs for prevention of diabetic nephropathy in vivo, (2) expand the in vivo studies in STZ-diabetic rats to a long term study (6-9 months) to include other endpoints of renal pathology, such as histology and morphometry, glucose tolerance and insulin sensitivity, and renal function, and (3) expand the in vivo studies to include another animal model of diabetes, the db/db mouse which spontaneously develops type II diabetes. The long-term commercial goal is to develop an orally active drug which can be given to both type I and type II diabetics to attenuate the renal damage caused by chronic hyperglycemia, and also attenuate other vascular complications of diabetes. [unreadable] [unreadable]